US3280115A - Steroid lactones and lactols and preparation thereof - Google Patents

Steroid lactones and lactols and preparation thereof Download PDF

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US3280115A
US3280115A US272224A US27222463A US3280115A US 3280115 A US3280115 A US 3280115A US 272224 A US272224 A US 272224A US 27222463 A US27222463 A US 27222463A US 3280115 A US3280115 A US 3280115A
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androstene
solution
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water
epoxy
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Bertin Daniel
Perronnet Jacques
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Sanofi Aventis France
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Roussel Uclaf SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • the invention relates to a novel process for the preparation of lactones of w-(unsaturated steroid)-propionic acid in which the lactone radical is situated in the 16- or 17- position of the steroid.
  • the invention also relates to novel unsaturated steroid compounds having the formula wherein R is a radical selected from the group consisting of where R is selected from the group consisting of lower alkyl, phenyl lower alkyl and an acyl radical of an organic carboxylic acid having 1 to 7 carbon atoms and 1',1'-diethers of the said steroid wherein the group attached to the D ring is in the 16 or 17-position, with the exception of the lactone of w-(A -androstene-17fl-ol-3-one- 17a-yl)-propionic acid.
  • the invention further relates to novel intermediates of the steroid lactones of Formula I.
  • novel process of the invention for the preparation of a lactone selected from the group consisting of lactones of w-(unlsaiturated androstanes-l6;3ol- 16a-yl)propionic acid and lactones of w-(unsaturated androstanes-17fi-oll7a-yl)-propionic acid comprises reacting a compound selected from the group consisting of unsaturated androstane-16-ones and unsaturated androstane-17-ones with the Grignard derivative of a ketonide of 1,2-dihydroxy-4-halobutane having the formula wherein R and R are alkyl radicals having 1 to 10 carbon atoms and X is a halogen to form the corresponding ketonide of a member selected from the group consisting of 16oc-(3',4' dihydroxybutyl)-unsaturated androstane- 5 16fi-ols and 17w(3,4-dihydroxybutyl)-
  • a variation of the process of the invention resides in forming the desired lactone in one step from 166- or 17B-hydr0xy-16aor 17a-(3',4'-dihydroxybutyl)-unsaturated androstane by oxidizing the latter with chromic acid anhydride or a mixture of sulfuric acid and chromic acid.
  • This variation uses more economical reactants and gives higher yields;
  • the process of the invention is outlined in Table I; I
  • the enamine grouping will be simultaneously hydrolyzed to the free keto group when the ketonide intermediate is subjected to acid hydrolysis to free the hydroxyl groups.
  • the other keto group can also be protected by the formation of an enol ether.
  • Examples of suitable androstenes which can be used as starting materials for the process of the invention are A -androstene-3,17 dione, A -androstene-3,16 dione, A androstene-17-one, A -androstene-16-one, n -androstadiene-17-one, A -androstadiene-16-one.
  • novel steroid compounds of the invention have the formula wherein R is a radical selected from the group consisting where R isselected from the group consisting of lower alkyl, phenyl lower alkyl and an acyl radical of an organic carboxylic acid having 1 to 7 carbon atoms and 1,1-diethers of the said steroid wherein the group attached to the D ring is in the 16 or 17 position, with the exception of the lactone of w-(A -androstene-17,8-ol-3-one-17B-yl)- propionic acid. Certain of the compounds of Formula I possess anti-aldosteronic activity.
  • a preferred mode of the process of the invention for producing the lactone of w-(M-androstene-l7B-ol-3-onel7u-yl)-propionic acid comprises reacting A -androstene- 3,17dione with a secondary amine selected from the group consisting of dilower alkyl amine, pyridine, pyrrolidine, and morpholine, preferably pyrrolidine in a lower alkanol, such as methanol to form the corresponding 3-enamino-A -androstadiene-17-one, reacting the latter with a magnesium derivative of a ketonide of 1,2-dihydroxy-4-halo-butane, preferably a magnesium derivative of 1,2-isopropylidenedioxy-4-brcmo-butane is a solvent, such as a mixture of either and benzene to form the corresponding ketonide of the 3-enamino-17a-(3',4- dzihydroxybutyl)-A -
  • 17a (3',4-dihydroxybutyl)-A -androstene-17fl-ol-3-one can be oxidized with chromic acid anhydride in an aqueous acetic acid solution or a solution of sulfuric and chromic acids in acetone to form the lactone of w-(A -androstene-17/3-ol-3-one- 17a-yl)- propionic acid.
  • the process is illustrated in Table II.
  • R has the above definition and R and R are lower alkyl radicals having 1 to 10 carbon atoms and R and R are lower alkyl radicals having 1 to 7 carbon atoms and when taken together with the nitrogen atom are selected from the group consisting of pyrrolidyl, morpholin-o and piperidino.
  • the lactone of m-(A -3.I1dI'OS[6I1- l6fl-ol-3-one-16a-yl)-prop ionic acid can be prepared by starting with A -androstene-3,16-dione to form 3-enamino- A -andr0stadiene-16-one, then the ketonide of 3-enamino- 16cc (3',4' dihydroxybutyl) A -androstadiene-16fl- 01,160 (3,4 dihydroxybutyl)-A -androstene-16B-ol-3- one, 1',16/3 epoxy 16u(lg-hydroxypropyl)-A -andr0- stene-3one and finally the lactone of w-(A -androstenel 6,8-ol-3--one-16a-yl)-propionic acid.
  • Table III The process is illustrated in Table III.
  • A) l oggl gnrcmfzifil can be easily prepared from 1,16;3- or l7fl-epoxy-l6otor 17a-(l'g-hydroxylpropyl)-A -androstene-3-one by a numher of the usual means of producing ethers and esters.
  • the corresponding l',16fior 17/3-epoxy-16aor Not-(1'5- acyloxypropyl)-A -androstene-3-one can be prepared.
  • the corresponding ethers can be produced by reacting the said epoxy compounds with the desired alcohol in the presence of an acid or the desired halide derivative in the presence of silver oxide.
  • the corresponding diether of the said epoxy compound can be easily prepared by reacting the said epoxy compound in the presence of ammonium periodate.
  • the compounds of Formula I are epimeric.
  • the epimer having the lower rotatory power is designated as Epimer A while the epimer having the higher rotatory power is designated as Epimer B.
  • the A and B epimer can be isolated by the customary methods.
  • ketonides of 1,2-dihydroxy-4-halo-butane which are used in the first step of the process of the invention are more fully described in commonly assigned, copending U.S. application Serial No. 272,230 filed on even date herewith.
  • Example I Preparation of 1,2-is0pr0pylidenedioxy- 4-brom0-butane STEP A: PREPARATION OF 1,2-ISOPROPYLIDENE- DIOXY--HYDROXY-BUTANE A mixture of 250 gm. of 1,2,4-trihydroxy-butane, 3 liters of acetone and 25 cc. of 65% perchloric acid was prepared and was allowed to stand at room temperature for about 2 hours under a nitrogen atmosphere with agitation. 65 gm. of sodium carbonate were added and the agitation was continued for another hour. The reaction mixture was filtered and 1.5 cc. of triethylamine were added to the filtrate.
  • the product was soluble in alcohol and acetone, insoluble in water and dilute aqueous alkalis while dilute aqueous acids decomposed it.
  • This compound was soluble in chloroform and insoluble' in water and dilute aqueous alkalis while dilute aqueous acids decomposed it.
  • 1,2 isopropylidenedioxy 4- hydroxy-butane could be reacted with acetic acid anhydride in pyridine to form the liquid acetate of 1,2-isopropylidenedioxy-4-hydroxy-butane having a boiling point of 205 C. at 760 mm. Hg and an index of refraction 12 1.430.
  • the product was soluble in chloroform, slightly soluble in ether and insoluble in water and dilute aqueous alkalis while dilute aqueous acids decomposed it.
  • STEP C PREPARATION OF 1,2-I-SPROPYLIDENEDIOXY- tl-BROMO-BUTA NE 280 gm. of lithium bromide were introduced into 1,400 cc. of acetone and 140 gm. of the mesylate of l,2-isopropylidenedioxy-4-hydroxy-butane and 7.5 cc. of triethylamine were added. The reaction mixture was heated to reflux under agitation for a period of about 5 hours. After 1,500 cc. of water were added, the organic phase was separated and the hydro-acetonic phase was extracted with ether. The ethereal extract was dried and concentrated under nitrogen.
  • the product was soluble in acetone and chloroform and insoluble in water and dilute aqueous alkalis while dilute aqueous acids decomposed it.
  • This product was soluble in chloroform, alcohol and water.
  • the product was soluble in benzene and chloroform, slightly soluble in alcohols and in ether and insoluble in water and dilute aqueous alkalis while dilute aqueous acids saponified it.
  • the starting compound was prepared according to the method described by Fajkos et al., Chem. Listy., 47, 1207 (1953).
  • STEP B PREPARATION OF 16a-(3,4-DIHYDROXY- BUTYL) -A -ANDR0STENE-16B-OL-3-ONE 2.04 gm. of magnesium were introduced into 30 cc. of ether and several milliliters of a solution of 16.72 gm. of 1,2-isopropylidenedioxy-4-bromo-butane in 80 cc. of ether were added slowly under dry nitrogen and under agitation. After refluxing had commenced, in about one hour, the said solution was combined with a solution of 7.22 gm. of 3-pyrrolidyl-A -androstadiene- 16-one in 80 cc. of benzene.
  • the reaction mixture was maintained under agitation and at room temperature for a period of about 21 hours and then 100 cc. of a saturated solution of ammonium chloride were slowly added under agitation.
  • the organic phase was separated, washed with water, dried over magnesium sulfate and concentrated under nitrogen.
  • the last traces of benzene were entrained by methanol and a methanolic suspension was obtained which was cooled to 0 C.
  • the crystals formed were vacuum filtered, washed with methanol and dried. 3.56 gm. of the acetonide of raw 3-pyrrolidyl-16ot-(3',4-dihydroxybutyl)-A -androstadiene-l6fi-ol were obtained.
  • a second lot of 0.48 gm. of product was obtained from the mother liquors.
  • the entire amount of product was recrystallized from isopropyl ether to obtain a product having a melting point towards 204 C. which was used as such for the next step of the synthesis.
  • This product was soluble in alcohol, chloroform, ethyl acetate, slightly soluble in benzene and insoluble in water.
  • STEP C PREPARATION OF 1',16B-EPOXY-16a(1- HYDROXYPROPYL) -A -ANDROS TENE3-ONE mg. of 1Got-3,4-dihydroxy-butyl)-A -androstene- 16,8-ol-3-one were dissolved in 10 cc. of tert.-butanol and a solution of 300 mg. of periodic acid, 10 cc. of water and 75 mg. of lithium carbonate was added thereto. The resulting mixture was subjected to agitation at room temperature for a period of about 3 hours and then water was added thereto. The crystals formed were vacuum filtered, washed with water and dried. 118 mg.
  • This compound was soluble in alcohol and chloroform and insoluble in water and dilute aqueous acids and alkalis.
  • STEP D PREPARATION OF THE LACTONE OF m-(A AlNDROSTENE-l6/3-OL-3-ONE16a-YL)-PROPIONIC ACID 140 mg. of 1,16B-epoxy-16a-(1-hydroxypropyl-A androstene-3-one were placed in suspension in 10.5 cc. of acetone and 3.5 cc. of water. The solution was cooled to 0 C. and then under agitation 0.15 cc. of a sulfochromic acid solution of 135 gm. of chromic acid, 115 cc. of sulfuric acid and water to make 500 cc. of solution Was added.
  • This compound was soluble in alcohol, acetone, benzene and chloroform, slightly soluble in ether and insoluble in water and dilute aqueous acids and alkalis.
  • Example II Prep:aratin of the lactone of w-(A -androstene-J7B-0l-3-0ne-17a-yl) -propionic acid
  • STEP A PREPARATION OF 3-PYRROLIDYL-A3'5- ANDROSTADIENE-17-ONE 10 gm. of A ,17-dione were introduced under nitrogen into 200 cc. of methanol and cc. of pyrroli-dine were added under agitation. The solution was maintained under an atmosphere of nitrogen and under agitation at room temperature for a period of 15 to 20 minutes. The precipitate formed was vacuum filtered, triturated with methanol and dried. 11.6 gm, of raw 3-pyrrolidyl-A androstadiene-17-one having a melting point of 224 C. were obtained which was used as such for the following step of the synthesis.
  • the product was soluble in benzene and insoluble in water and alcohol.
  • the starting compound of this step was prepared according to the method described by Ruzicka et al., Helv. Chim. Acta., 18, 986 (1935).
  • STEP B PREPARATION OF 17a-(3',4'-DIHYDROXY- BUTYL) -A -ANDROSTENE-l'i'B-OL-Et-ONE 5.5 gm. of magnesium were introduced into 40 cc. of ether and several milliliters of a solution of 47 gm. of 1,2-isopropylidenedioxy-4-bromo-butane in 200 cc. of ether were introduced slowly under dry nitrogen and under agitation. When reflux started the remainder of the said solution and a solution of 11.7 gm. of 3-pyrrolidyl-A -androstadiene-17- one in 200 cc. of benzene were added simultaneously over a period of about 50 minutes.
  • the reaction mixture was maintained in a closed vessel under agitation and at room temperature for a period of 65 hours. Then the mixture was cooled to a temperature between about 0 and C. and 50 cc, of a saturated solution of ammonium chloride were introduced. Agitation was continued for a period of about 30 minutes and then water was added thereto and the mixture was decanted. The organic solution was separated, washed with water and dried over magnesium sulfate. 50 mg. of hydroquinone were added thereto and the mixture was concentrated under nitrogen. 30 gm.
  • the raw acetonide of 3-pyrrolidyl-17a-(3,4'-dihydroxy-butyl)-A -androstadiene-175-01 was introduced into 200 cc. of N hydrochloric acid and agitated under an atmosphere of nitrogen for a period of one hour. The undissolved part was separated and washed several times with chloroform containing methanol. The combined wash solutions Were extnacted with 50 cc. of N hydrochloric acid. The aqueous phases were combined, brought to alkalinity under nitrogen and under agitation by the addition of sodium hydroxide solution. The preci-pitate formed was separated and extracted with chloroform.
  • the raw 3-pyrrolidyl-17a-(3,4'-di-hydroxybutyl)-A androstadiene-l7fi-ol was added to a solution of 36 cc. of acetic acid, 36 cc. of water and 12 gm. of sodium acetate and the resulting solution was agitated for 30 minutes at room temperature. Then 70 cc. of sodium hydroxide solution and 500 cc. of methanol were added in order to dissolve the precipitate formed, and the solution was neutralized by the addition of about 20 cc. of concentrated hydrochloric acid. The solution was then concentrated under nitrogen until a precipitate appeared and then was extracted with methylene chloride.
  • the extract was washed with water, dried upon magnesium sulfate and concentrated to obtain 8.4 gm. of raw 1704- (3,4'-dihydroxybutyl)-A -androstene-17 8 ol one.
  • the product was purified by subjecting it to chromatography through magnesium silicate with elution with methylene chloride containing 8% of methanol, crystallization and recrystallization from ether to obtain 2.6 gm. of purified product.
  • a new purification was effected by recrystallization from iso-propanol to obtain 980 mg. of 17a-(3',4- dihydroxybutyl)-A -androstene-17/3 ol 3 one having a melting point of 194 C.
  • a second lot of 840 mg. of product could be obtained from the mother liquors.
  • This compound was soluble in alcohol, slightly soluble in benzene and chloroform and insoluble in water and dilute aqueous alkalis.
  • STEP C PREPARATION OF 1,17B-EPOXY-17a.-(1- HYDROXYPROPYL) -A -A.NDRO STENE-3-OENE 700 mg. of 17a-(3,4'-dihydroxybutyl)-A -androstene- 17B-ol-3-one were dissolved in 70 cc. of tert.-butanol and 1.5 cc. of water. Then under agitation a solution of 1.4 gm. of periodic acid, 70 cc. of water and 6 cc. of 1 N sodium hydroxide was added. The reaction mixture was allowed to stand in a closed vessel under agitation for a period of about 2 hours and then was added to water.
  • the precipitate formed was extracted with chloroform and the organic solutions were washed with saturated salt solution, dried over magnesium sulfate, filtered and concentrated. The residue was taken up with ether and allowed to crystallize and the crystals were vacuum. filtered. The crystals obtained were dissolved in benzene and the solution was filtered, concentrated and then isopropyl ether was added thereto. The mixture was then allowed to stand for crystallization.
  • This compound was soluble in alcohol, benzene and chloroform, slightly soluble in ether and isopropyl ether,
  • STEP D PREPARATION OF THE LACTONE OF CLJ"(A4' ANDROS'TENE-17B-OL-3-ONE-17a-YL) -PROPIONIC ACID 100 mg. of 1,17fi-epoxy-17a-(1-hydroXypropyl)-A androstene-3-one were dissolved in a mixture of 4 cc. of acetone and 1.5 cc. of water and 0.1 cc. of a solution of 135 gm. of chromic acid, 115 cc. of sulfuric acid and enough water to form a final solution of 500 cc. were slowly added thereto under agitation. At the end of 30 minutes 1 cc.
  • the product was taken up with methylene chloride and the solution was centrifuged and concentrated. A little bit of petroleum ether was added thereto and the solution was allowed to stand for crystallization. The crystals formed were vacuum filtered to obtain 70 mg. of the raw lactone of w-(M-androstene-17,8-ol-3-one17a-yl)-propionic acid which was purified by recrystallization from isopropyl ether containing a little bit of methylene chloride. The purified product had a melting point of 165 C.
  • the product was soluble in chloroform, slightly soluble in isopropyl ether and insoluble in water.
  • the product was soluble in ether, benzene and chloroform, slightly soluble in cyclohexane and insoluble in water and dilute aqueous acids and alkalis.
  • the reaction mixture was maintained under agitation for a period of about 5 hours at room temperature and then methanol, water and ammonium hydroxide solution in order to neutralize the largest part of the acetic acid were added successively thereto.
  • the solution was extracted with methylene chloride and the extract was washed with a solution of sodium bicarbonate and with water, dried and concentrated to dryness under vacuum. The residue was taken up with acetone containing one drop of sulfuric acid and water was added to the resulting solution.
  • the precipitate formed was extracted, dried and crystallized from isopropyl ether and the crystals were vacuum filtered and dried. 15 mg.
  • Example VI Preparation of the lactone of (xi-(A androstene-Z 7B-0l-3-0ne-1 70t-yl) -propionic acid 750 mg. of 17a-(3',4-dihydroxybutyl)-A -androstene- 17fi-ol-3-one produced in step B of Example III were dissolved in 12 cc. of acetic acid and after cooling the resulting solution to 15 C., 10 cc. of a solution composed of 4 gm. of chromic acid anhydride and 5 cc. of water in enough acetic acid to make 50 cc. of solution were added thereto. The reaction mixture was subjected to agitation overnight at room temperature.
  • Example VII Preparation of 1',17[a-ep0xy-17a-(1'- methoxypropy l) -A -andrstene-3-0ne
  • 1 gm. of 1,17fl-epoxy17a-(l'g-hydroxypropyD-M- androstene-3-one were dissolved in 25 cc. of methanol and 0.5 cc. of a normal solution of sulfuric acid was added. The mixture was heated to reflux for a period of one hour and then water was slowly added until crystallization commenced. The crystals formed were vacuum filtered, washed with water, dried to obtain 957 mg. of raw 1,17 8- epoxy-17a-( lg-methoxypropyl) -A -androstene-3-one.
  • the product was soluble in ether and chloroform, slightly soluble in cyclohexane and methanol, very slightly soluble in alcohol, and insoluble in water and dilute aqueous acids and alkalis.
  • the methanolic liquors obtained from the washings of 1,900 mg. of raw 1',17p-epoxy-17u-(lg-methoxypropyn- A -androstene-3-one were combined and evaporated.
  • the crystalline residue was taken up with hot methanol and the solution obtained was cooled and allowed to stand until crystallization occurred.
  • the crystals obtained were vacuum filtered, dried, recrystallized by heating and cooling in methanol, vacuum filtered and dried.
  • the product was soluble in ether, benzene and chloroform, slightly soluble in cyclohexane and methanol, very slightly soluble in alcohols and insoluble in water and dilute aqueous acids and alkalis.
  • the product was soluble in benzene and chloroform, slightly soluble in alcohol, .ether and cyclohexane and insoluble in water and hexane.
  • the above product was the A epimer, having a lower rotatory power, of the above compound.
  • the mixture of epimers rich in B epimer having a higher rotatory power was isolated from the mother liquors and the liquors of recrystallization, which were combined, and subjected to chromatography through magnesium silicate with elution with benzene containing 0.75% of acetone.
  • the B epimer has not been crystallized.
  • Example IX Preparation of 1,17,8-ep0xy-17oc-(1- acetoxypropyl)-A -andr0stene-3-0ne 689 mg. of 1,17,6-epoxy-l7a(l'g-hydroxypropyD-M- androstene-El-one were introduced into 1 cc. of pyridine and while the mixture was subjected to agitation, 1 cc. of acetic anhydride was added. The reaction mixture was subjected to agitation at room temperature for a period of about 65 hours and then was added to a mixture of water and ice and 1 cc. of pyridine. The solution was extracted with a mixture of methylene chloride and ethanol.
  • a first yield of 273 mg. of the product were obtained having a melting point of 132-133 C. and a specific rotation [a] :
  • the product of the second lot (A-l-B) was soluble in ether, benzene, chloroform, slightly soluble in cyclohexane and insoluble in water and isopropyl ether.
  • 17, and 140 mg. of a lot having a melting point of 134 C. and a specific rotation [a] +59 were also obtained.
  • the said product was taken up with hot benzene, filtered, concentrated, methanol added and cooled to 0 C.
  • the crystals formed were vacuum filtered, washed with methanol and dried :to obtain 150 mg. of the raw lglg-ether oxide of 1g,17,8-epoxy-17a-(lg-hydroxypropyl)-A -androstene-3-0ne which was purified by recrystallization in benzene with the addition of methanol.
  • the product was soluble in benzene and chloroform, slightly soluble in alcohols and insoluble in water, methanol and dilute aqueous acids and alkalis.
  • a process for the preparation of the lactone of w-(A -androstene-l7[3-ol-3-one 17a yl)-propionic acid which comprises reacting A -androstene-3,17-dione with a secondary amine selected from the group consisting of dilower alkylamine, morpholine, pyridine and pyrrolidine to form the corresponding 3-enamino-A -androstadiene- 17-one, reacting the latter with a magnesium derivative of a ketonide of 1,2-dihydroxy-4-halo-butane having the formula o to R2 R3 wherein R and R are alkyl radicals having 1 to 10 carbon atoms and X is a halogen to form the corresponding ketonide of 3-enamino-l7a-(3',4'-dihydroxybutyl)-A -androstadiene-175-01, hydrolyzing the latter to form 17a-(3',4'-dihydroxybuty1)
  • a process for the preparation of the lactone of w-(A -androstene-17fl-ol-3-one 17a yl)-propionic acid which comprises reacting A -androstene-3,17-dione with a secondary amine selected from the group consisting of dilower alkylamine, morpholine, pyridine and pyrrolidine to form the corresponding 3-enamino-A -androstadiene-17- one, reacting the latter with a magnesium derivative of a ketonide of 1,2-dihydroxy-4-halo-butane having the formula wherein R and R are lalkyl radicals having 1 to 10 carbon atoms and X is a halogen to form the corresponding ketonide of 3-enamino-17a-(3',4'-dihydroxybutyl)-A androstadiene-Ufl-ol, hydrolyzing the latter to form 1700-- (3',4'-dihydr-oxybutyl)-A -

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US272224A 1962-04-18 1963-04-11 Steroid lactones and lactols and preparation thereof Expired - Lifetime US3280115A (en)

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US (1) US3280115A (fr)
FR (2) FR1334968A (fr)
GB (1) GB1036088A (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2781342A (en) * 1952-05-17 1957-02-12 Upjohn Co Steroid enamines
US2938031A (en) * 1958-12-11 1960-05-24 Searle & Co 17-carboxyalkylated 3-oxygenated 6-methylandrosten-17-ol lactones and intermediates
US3137690A (en) * 1963-09-26 1964-06-16 Searle & Co 17beta-hydroxy-3-oxoandrost-4-en-17alpha-ylpropionaldehyde lactol and delta1, delta6, delta1, 6, 19-nor and 7alpha-acetylthio congeners

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2781342A (en) * 1952-05-17 1957-02-12 Upjohn Co Steroid enamines
US2938031A (en) * 1958-12-11 1960-05-24 Searle & Co 17-carboxyalkylated 3-oxygenated 6-methylandrosten-17-ol lactones and intermediates
US3137690A (en) * 1963-09-26 1964-06-16 Searle & Co 17beta-hydroxy-3-oxoandrost-4-en-17alpha-ylpropionaldehyde lactol and delta1, delta6, delta1, 6, 19-nor and 7alpha-acetylthio congeners

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FR1334968A (fr) 1963-08-16
GB1036088A (en) 1966-07-13
FR1979M (fr) 1963-08-19

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